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and since then over 100 different mutations in this gene have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> These mutations may be nonsense or missense&#44; and not all have the same pathophysiological effects&#46; The former are usually more serious&#44; as they produce a truncated protein that is dysfunctional because it is a different length than normal&#46; Missense mutations cause substitution of an amino acid but the protein remains complete&#46; In this case the biological effects on protein function are unclear&#44; and <span class="elsevierStyleItalic">in vitro</span> functional studies are needed to ascertain their importance&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Mutations in the <span class="elsevierStyleItalic">SCN5A</span> gene can lead to a decrease in sodium current &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">Na</span>&#41; in the cardiac action potential&#44; either through quantitative decrease &#40;failure in expression&#41; or through qualitative dysfunction of the channel&#46; However&#44; mutations are found in only 18&#8211;30&#37; of patients<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and in only 38&#37; of familial cases&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This low incidence may be explained by genetic heterogeneity&#44; i&#46;e&#46; mutations in other genes that are associated with BS&#44; as well as many others presumably yet to be discovered&#44; including&#58; &#40;1&#41; <span class="elsevierStyleItalic">GPD1-L</span>&#44; the gene that codes for glycerol-3-phosphate dehydrogenase 1 like peptide&#44; which is responsible for the transport of Na<span class="elsevierStyleInf">V</span>1&#46;5 to the cell surface and&#44; when mutated&#44; leads to a 31&#37; reduction in the quantity of channels available in the membrane and a 50&#37; reduction in sodium current&#44; resulting in BS<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#59; &#40;2&#41; mutations in cardiac calcium channel genes &#40;<span class="elsevierStyleItalic">CACNA1c</span> and <span class="elsevierStyleItalic">CACNB2b</span>&#41; associated with an overlapping entity&#44; short QT syndrome with Brugada ECG pattern<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#59; and &#40;3&#41; mutations in the <span class="elsevierStyleItalic">KCNE3</span> gene&#44; which modulates the function of the K<span class="elsevierStyleInf">V</span>4&#46;3 channel&#44; which is responsible for the transient potassium outward current &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">TO</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Apart from those recently described in the <span class="elsevierStyleItalic">SCN5A</span> gene&#44; all these mutations have made it necessary to widen the original idea of BS as a &#8220;pure&#8221; sodium channelopathy to the currently accepted concept of it as a channelopathy of phase 1 of the cardiac action potential due to an imbalance in one of the different ion currents &#40;sodium&#44; potassium or calcium&#41;&#44; caused by mutations in either ion channel genes or in genes coding for proteins associated with the activity or transport of these currents&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Diagnosis of BS</span><p id="par0020" class="elsevierStylePara elsevierViewall">Diagnosis of BS is currently only considered definitive when a type 1 Brugada ECG pattern is observed in at least two right precordial leads&#44; in the presence or absence of a sodium-channel blocking agent&#44; in conjunction with one or more of the following&#58; documented ventricular fibrillation &#40;VF&#41;&#44; documented ventricular tachycardia &#40;VT&#41;&#44; a family history of sudden cardiac death at &#60;45 years old&#44; type 1 ECG in family members&#44; inducibility of VF&#47;VT with programmed electrical stimulation in electrophysiological study&#44; syncope&#44; or nocturnal agonal respiration&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">From gene to electrocardiogram</span><p id="par0025" class="elsevierStylePara elsevierViewall">There are two theories to explain the electrocardiographic manifestations of BS&#58; &#40;1&#41; delayed conduction in the free wall epicardium of the right ventricular outflow tract&#59; &#40;2&#41; premature repolarization of the right ventricular epicardial action potential&#59; or a combination of the two&#46; In the first&#44; asynchronous activation of the epicardium in relation to the endocardium&#44; due to dysfunction of an ion channel &#40;Na<span class="elsevierStyleInf">V</span>1&#46;5 or another&#41;&#44; creates a voltage gradient between the two layers of cells&#46; In the second &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; dysfunction of a channel &#40;Na<span class="elsevierStyleInf">V</span>1&#46;5 or another&#41; leads to an imbalance in phase 1 that favors repolarization due to the disproportionate <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">TO</span> current &#40;positive outward current&#41;&#44; with the result that the membrane repolarizes beyond the voltage at which L-type calcium channels are activated and phase 2 of the action potential thus fails&#46; In both models a transmural voltage gradient is generated between the epicardium and the endocardium that appears on the ECG as a coved ST-segment elevation of &#8805;2<span class="elsevierStyleHsp" style=""></span>mm &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mV&#41;&#44; followed by a negative T wave &#40;type 1 Brugada ECG&#41; that acts as an arrhythmic substrate for phase 2 reentry&#46; Both hypotheses explain the preferential involvement of the right ventricular outflow tract since the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">TO</span> current has greater functional expression in the epicardium of this region&#46; The repolarization alterations on the ECG that are diagnostic of BS reflect dysfunction of the ventricular fast response action potential&#44; which is also responsible for depolarization of atrial myocytes and Purkinje fibers &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> It can therefore be hypothesized that the action potential dysfunction responsible for the repolarization disturbances described above may also lead to increases&#44; or even subclinical or clinical disturbances&#44; in intra-atrial&#44; atrioventricular and intraventricular conduction&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Difficulties in the diagnosis of BS</span><p id="par0030" class="elsevierStylePara elsevierViewall">A diagnosis of BS is simple in its most characteristic form of presentation&#44; i&#46;e&#46; spontaneous type 1 repolarization pattern in the right precordial leads together with aborted cardiac arrest&#46; Type 1 repolarization pattern with no other criteria should be described as idiopathic Brugada ECG &#40;not Brugada syndrome&#41;&#44; and there is considerable controversy concerning the appropriate clinical approach&#46; A wide range of differential diagnoses that can mimic the BS ECG alterations should be considered &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> but it should be borne in mind that the first symptom that confirms a diagnosis of BS may be catastrophic&#58; cardiac arrest is the first manifestation in 77&#37; of patients&#46; There are also difficulties with diagnosis in cases of borderline or Brugada-like repolarization patterns&#46; Besides type 1 Brugada ECG&#44; there are two other repolarization patterns associated with BS &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#58; type 2 &#40;&#8805;2<span class="elsevierStyleHsp" style=""></span>mm J-point elevation&#44; downsloping ST segment but at least 1<span class="elsevierStyleHsp" style=""></span>mm above the isoelectric line&#44; and positive or biphasic &#40;&#8216;saddle-back&#8217;&#41; T wave&#59; and type 3&#44; with &#8805;2<span class="elsevierStyleHsp" style=""></span>mm J-point elevation and &#60;1<span class="elsevierStyleHsp" style=""></span>mm ST-segment elevation&#44; coved or saddle-back or both&#46; According to the consensus conference on Brugada syndrome&#44; types 2 and 3 are merely suggestive and not diagnostic&#44; a recommendation that is not followed by all authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> Whether only type 1&#44; or all three types of pattern&#44; are taken to be diagnostic obviously affects the sensitivity and specificity of the ECG to detect BS&#44; sensitivity being greater when all three are used and specificity being higher with only type 1&#46; Type 3 pattern is virtually indistinguishable from the incomplete right bundle branch block found in the young&#59; disregarding it could have catastrophic results&#44; but an incorrect diagnosis of BS would place an enormous burden on a healthy individual and their family&#44; with serious consequences for their personal&#44; social&#44; and professional life&#46; This dilemma has aroused controversy in the literature and is presumed to have &#8220;contaminated&#8221; some databases with healthy individuals&#44; which would explain the significant differences in reported prognosis for this entity&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">When diagnosis is confirmed in any index case&#44; all family members who might be affected should be tested with baseline ECG and&#47;or provocation testing&#46; Baseline ECG alone is insufficient&#44; since 51&#37; of affected individuals fluctuate between diagnostic and non-diagnostic ECGs&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Provocation testing with sodium channel blockers such as flecainide&#44; ajmaline or procainamide is thus essential to detect intermittent or occult forms of the disease&#44; although little is known of their sensitivity&#44; specificity and reproducibility&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Signal-averaged ECG</span><p id="par0040" class="elsevierStylePara elsevierViewall">Signal-averaged ECG &#40;SAECG&#41; is a computer-based technique that is able to detect QRS abnormalities that are too subtle for conventional ECG&#46; This exam &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41; shows the arithmetic mean of the sum of multiple &#40;usually 200&#41; QRS complexes&#44; obtained over a period of approximately five minutes with as little background noise as possible&#46; The process increases the signal-to-noise ratio of the selected cardiac complexes so that signals of the order of one microvolt in the terminal QRS complex can be detected and measured to within a few milliseconds&#46; These signals are commonly known as ventricular late potentials&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Objectives</span><p id="par0045" class="elsevierStylePara elsevierViewall">The aims of the study were to construct a model to detect carriers of nonsense or missense <span class="elsevierStyleItalic">SCN5A</span> mutations with significant functional repercussions based on subclinical disturbances in intra-atrial&#44; atrioventricular and intraventricular conduction&#46; This is used to develop a score of disease probability which we suggest should be used in first-degree relatives of Brugada patients and in individuals with idiopathic Brugada ECG&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Of a total of 141 members of three different families including 55 carriers of two nonsense SCN5A mutations causing BS &#40;43 with Arg222STOP and 12 with Thr1754ProfsX32&#41;&#44; all those aged over 16 were studied&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The PR interval &#40;PR&#41; in DII and QT dispersion &#40;QTd&#41; between leads V1 and V3 were measured on conventional ECG&#44; calibrated so that 20<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>mV&#44; and with a velocity of 50<span class="elsevierStyleHsp" style=""></span>mm&#47;s&#46; Signal-averaged ECG was performed with time-domain analysis&#44; and the total duration of the filtered QRS complex &#40;fQRS&#41;&#44; the root-mean-square &#40;RMS40&#41; and the low-amplitude signal &#40;LAS&#41; were measured&#46; Two tests were developed to detect carriers&#58;</p><p id="par0060" class="elsevierStylePara elsevierViewall">&#40;1&#41; a screening test &#40;ScreenTest&#41; with PS &#40;the sum of PR and fQRS&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 &#40;the theoretical maximum of this interval in healthy individuals is 314<span class="elsevierStyleHsp" style=""></span>ms &#91;200<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>114&#93;&#44; 250<span class="elsevierStyleHsp" style=""></span>ms being 80&#37; of this figure&#41;&#59;</p><p id="par0065" class="elsevierStylePara elsevierViewall">&#40;2&#41; a diagnostic test &#40;DiagTest&#41; for the simultaneous fulfillment of four conditions&#58; PS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 and QTd<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10 and LAS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>26 and RMS40<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>29 &#40;the latter two cut-offs are approximately 70&#37; of the theoretical maximum in healthy carriers&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">The study population consisted of 113 individuals&#44; 42 of them carriers&#46; Significant differences in PR&#44; QTd&#44; fQRS&#44; RMS40 and LAS were found between carriers and non-carriers&#46; The <span class="elsevierStyleItalic">SCN5A</span> gene was associated with all these variables&#44; the strongest association being with PR &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Both tests were applied to 63 family members &#40;38 carriers&#41;&#46; The ScreenTest was positive in 38 of 38 carriers&#44; with eight false positives in 27 non-carriers &#40;sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; and specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#46;67&#37;&#41;&#46; From ROC curve analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41; a cut-off of PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>252&#46;5 shows sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; and specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#37; and a cut-off of PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>260 shows sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#46;7&#37; and specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>84&#37;&#46; The DiagTest was positive in 36 of 38 carriers&#44; with three false positives&#58; sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#46;74&#37; and specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>88&#46;89&#37;&#46; From ROC curve analysis a multivariate logistic model identifies a cut-off with sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37; and specificity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37;&#46; The area under the curve was 0&#46;927 &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; demonstrating that this test has an excellent ability to discriminate between carriers and non-carriers&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In the same group the sensitivity and specificity of the characteristic spontaneous repolarization pattern &#40;type 1 Brugada ECG&#41; to detect carriers were 52&#46;4&#37; and 97&#46;2&#37;&#44; respectively&#44; and the difference between the sensitivity of the DiagTest and of the typical repolarization pattern is statistically significant&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">In 2008 it was demonstrated that carriers of truncating &#40;nonsense&#41; <span class="elsevierStyleItalic">SCN5A</span> mutations have more symptomatic forms of BS&#44; and atrioventricular conduction disturbances were also described&#44; both through increased PR interval<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> and increased HV interval measured invasively during electrophysiological study&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> SAECG was proposed around the same time as a possible tool for arrhythmic risk stratification in BS&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">However&#44; this study is the first to propose incorporating conduction parameters into the diagnostic process&#46; As with long QT syndrome<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> and arrhythmogenic right ventricular cardiomyopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> the proposed test could be included in a score of disease probability &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; which we consider would be useful given the shortcomings discussed above of using patterns of ventricular repolarization in isolation and the clinical and social burdens arising from a diagnosis of BS&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">When there is clinical and&#47;or electrocardiographic suspicion of BS&#44; intra-atrial&#44; atrioventricular and intraventricular conduction times should be measured&#44; ideally with SAECG&#44; since the fast response cardiac action potential that is dysfunctional in BS is involved in all three&#46; Simultaneous detection of times above the normal-high limit of these three depolarization times &#40;in this study the limit used was 70&#8211;80&#37; of the theoretical maximum in healthy individuals&#41; may indicate the likelihood of the individual having the disease due to nonsense or missense mutations in <span class="elsevierStyleItalic">SCN5A</span> with significant functional impact&#46; We suggest their use in adult first-degree relatives of index cases when the results of genetic testing are not available&#46; Another possible use would be to calculate the probability of disease in individuals with idiopathic Brugada ECG or with arrhythmias and type 2 or 3 Brugada repolarization pattern&#46; In these cases&#44; the proposed score could support the diagnosis &#40;score 7&#41;&#44; raise suspicion &#40;score 6&#41;&#44; or render it unlikely &#40;score &#8804;5&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusion</span><p id="par0090" class="elsevierStylePara elsevierViewall">We have shown that the ScreenTest and DiagTest are more effective tools than the characteristic Brugada repolarization pattern to discriminate between carriers and non-carriers of nonsense <span class="elsevierStyleItalic">SCN5A</span> mutations&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">These tests may be useful in diagnosing this entity by determining the probability that a given repolarization pattern in fact corresponds to BS&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Limitations</span><p id="par0100" class="elsevierStylePara elsevierViewall">Our study has two major limitations&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0105" class="elsevierStylePara elsevierViewall">The number of carriers was relatively small and only two mutations were studied&#46; In order to prove the usefulness and reproducibility of the proposed score&#44; it will be necessary to apply it to other Brugada patients and their families&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The P wave and the PR interval were not measured with the precision of SAECG&#44; since the means to do so were not available to our group&#46; Measurement of the PS interval&#44; or the PR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fQRS wave&#44; entirely by SAECG &#40;without interference from the atrioventricular node&#41; could make the score even more effective&#46;</p></li></ul></p><p id="par0115" class="elsevierStylePara elsevierViewall">We accordingly urge all clinicians working with BS patients who may be interested in collaborating with this work to contact us&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diagnosis of Brugada syndrome &#40;BS&#41; currently requires documentation of a characteristic repolarization pattern &#40;type 1 Brugada ECG&#41;&#46; Mutations in the <span class="elsevierStyleItalic">SCN5A</span> gene&#44; which codes for sodium channel Na<span class="elsevierStyleInf">V</span> 1&#46;5&#44; are found in 38&#37; of familial cases of BS&#46; Sodium current dysfunction negatively affects the cardiac fast response action potential&#44; particularly in atrial and ventricular myocytes and in the fast-conducting Purkinje system&#46;</p> <span class="elsevierStyleSectionTitle">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To detect carriers of <span class="elsevierStyleItalic">SCN5A</span> mutations without using the characteristic repolarization pattern &#40;type 1 Brugada ECG&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of a total of 141 members of three different families including 55 carriers of two nonsense <span class="elsevierStyleItalic">SCN5A</span> mutations causing BS&#44; all those aged over 16 &#40;113 individuals&#44; 42 carriers&#41; were studied&#46; The PR interval &#40;PR&#41; and QT dispersion &#40;QTd&#41; between leads V1 and V3 were measured on conventional ECG&#46; Using signal-averaged ECG the total duration of the filtered QRS complex &#40;fQRS&#41;&#44; the root-mean-square &#40;RMS40&#41; and the low-amplitude signal &#40;LAS&#41; were measured&#46; The following procedures were developed to detect carriers&#58; &#40;1&#41; a screening test &#40;ScreenTest&#41; with PS &#40;PR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fQRS&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 &#40;250<span class="elsevierStyleHsp" style=""></span>ms is 80&#37; of the theoretical maximum in healthy individuals&#41;&#59; and &#40;2&#41; a diagnostic test &#40;DiagTest&#41; for the simultaneous fulfillment of four conditions&#58; PS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 and QTd<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10 and LAS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>26 and RMS40 &#8804;29 &#40;the latter two cut-offs are approximately 70&#37; of the theoretical maximum in healthy carriers&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Significant differences in PR&#44; QTd&#44; fQRS&#44; RMS40 and LAS were found between carriers and non-carriers&#46; The <span class="elsevierStyleItalic">SCN5A</span> gene was associated with all these variables&#44; the strongest association being with PR&#46; Both tests were applied to 63 family members &#40;38 carriers&#41;&#46; The ScreenTest was positive in 38 of 38 carriers&#44; with eight false positives in 27 non-carriers &#40;sensitivity &#91;SE&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; and specificity &#91;SP&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#46;67&#37;&#41;&#46; From ROC curve analysis a cut-off of PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>252&#46;5 shows SE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; and SP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#37; and a cut-off of PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>260 shows SE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#46;7&#37; and SP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>84&#37;&#46; The DiagTest was positive in 36 of 38 carriers&#44; with three false positives&#58; SE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#46;74&#37; and SP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>88&#46;89&#37;&#46; From ROC curve analysis a multivariate logistic model identifies a cut-off with SE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37; and SP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37;&#46; In the same group the SE and SP of the characteristic spontaneous repolarization pattern &#40;type 1 Brugada ECG&#41; to detect carriers were 52&#46;4&#37; and 97&#46;2&#37;&#44; respectively&#44; and the difference between the SE of the DiagTest and of the typical repolarization pattern is statistically significant&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The ScreenTest and DiagTest are more effective tools than the characteristic repolarization pattern to discriminate between carriers and non-carriers of these two nonsense <span class="elsevierStyleItalic">SCN5A</span> mutations&#46; We suggest their use in first-degree relatives of Brugada patients when the results of genetic testing are not available&#44; in a score of disease probability in individuals with idiopathic Brugada ECG&#44; and in patients with arrhythmias or other Brugada-related symptoms presenting type 2 or type 3 Brugada ECG&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Atualmente&#44; o diagn&#243;stico da S&#237;ndrome de Brugada &#40;SB&#41; obriga &#224; documenta&#231;&#227;o do padr&#227;o eletrocardiogr&#225;fico de repolariza&#231;&#227;o caracter&#237;stico denominado tipo 1&#46; Em 38&#37; dos casos familiares desta entidade encontra-se uma muta&#231;&#227;o do gene <span class="elsevierStyleItalic">SCN5A</span> respons&#225;vel pela s&#237;ntese do canal de s&#243;dio Na<span class="elsevierStyleInf">V</span>1&#46;5&#46; A disfun&#231;&#227;o desta corrente de s&#243;dio repercute-se no potencial de a&#231;&#227;o card&#237;aco de resposta r&#225;pida&#44; fundamentalmente nos mi&#243;citos auriculares&#44; nas fibras de Purkinje e nos mi&#243;citos ventriculares&#46;</p> <span class="elsevierStyleSectionTitle">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Detetar portadores de muta&#231;&#227;o do <span class="elsevierStyleItalic">SCN5A</span> sem recorrer ao padr&#227;o de repolariza&#231;&#227;o no ECG&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A partir de 3 fam&#237;lias e de um total de 141 elementos&#44; dos quais 55 portadores &#40;P&#43;&#41; de duas muta&#231;&#245;es <span class="elsevierStyleItalic">non-sense</span> espec&#237;ficas do <span class="elsevierStyleItalic">SCN5A</span> causadoras de SB&#44; foram estudados os maiores de 16 anos &#40;113 elementos&#47;42 P&#43;&#41;&#46; Foi medido no ECG o intervalo PR &#40;PR&#41; em DII e dispers&#227;o QT &#40;dQT&#41; entre V1 e V3&#46; No ECG de alta resolu&#231;&#227;o &#40;ECGAR&#41; determinado o QRS filtrado &#40;QRSf&#41;&#44; <span class="elsevierStyleItalic">root-mean square</span> &#40;RMS40&#41; e <span class="elsevierStyleItalic">low-averaged signal</span> &#40;LAS&#41;&#46; Para detetar P&#43; foi criado&#58; 1&#41; um teste de rastreio &#40;TesteRas&#41; constitu&#237;do pelo intervalo PS &#40;PR&#43;QRSf&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 &#40;250<span class="elsevierStyleHsp" style=""></span>ms corresponde a 80&#37; do valor te&#243;rico m&#225;ximo deste intervalo em saud&#225;veis&#41; e 2&#41; um teste diagn&#243;stico &#40;TesteDx&#41; que resulta do cumprimento simult&#226;neo de 4 condi&#231;&#245;es&#58; PS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 e dQT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10 e LAS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>26 e RMS40<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>29 &#40;estes 2 &#250;ltimos valores correspondem aproximadamente a 70&#37; do valor te&#243;rico m&#225;ximo em saud&#225;veis&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Encontradas diferen&#231;as significativas entre os P&#43; <span class="elsevierStyleItalic">versus</span> n&#227;o portadores &#40;P-&#41; do PR&#44; da dQT&#44; do QRSf&#44; do LAS e da RMS40&#46; O gene est&#225; associado a todas estas vari&#225;veis&#44; sendo a associa&#231;&#227;o mais forte com o PR&#46; A 63 elementos &#40;38 P&#43;&#41; foi aplicado o TesteRas e o TesteDx&#46; O TesteRas foi positivo em 38 de 38 P&#43; com 8 falsos positivos em 27 P- &#40;sensibilidade &#91;S&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; e especificidade &#91;E&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#44;67&#37;&#41;&#46; Na curva Roc para este teste o <span class="elsevierStyleItalic">cut-off</span> PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>252&#44;5 tem S<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37; e E<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#37; e o <span class="elsevierStyleItalic">cut-off</span> PS&#61;260 tem S<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#44;7&#37; e E<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>84&#37;&#46; O TesteDx foi positivo em 36 de 38 P&#43; com 3 falsos positivos&#58; S<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#44;74&#37; e E<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>88&#44;89&#37;&#46; Por modelo log&#237;stico multivariado identifica-se um <span class="elsevierStyleItalic">cut-off</span> atrav&#233;s da curva Roc com S<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37; e E<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37;&#46; A S e E de diagn&#243;stico do ECG espont&#226;neo usando o padr&#227;o de repolariza&#231;&#227;o tipo 1 no mesmo grupo de doentes foram de 52&#44;4&#37; e 97&#44;2&#37;&#44; respetivamente &#40;a diferen&#231;a de S entre o TesteDx e o padr&#227;o de repolariza&#231;&#227;o no ECG &#233; estatisticamente significativa&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#245;es</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">O TesteRas e o TesteDx s&#227;o uma ferramenta mais eficaz do que o padr&#227;o de repolariza&#231;&#227;o t&#237;pico para distinguir entre P&#43; e P- destas duas muta&#231;&#245;es <span class="elsevierStyleItalic">non-sense</span> do <span class="elsevierStyleItalic">SCN5A</span>&#46; Sugerimos a sua utiliza&#231;&#227;o em familiares diretos de casos &#237;ndice com SB&#44; quando o resultado gen&#233;tico &#40;ainda&#41; n&#227;o est&#225; dispon&#237;vel e num <span class="elsevierStyleItalic">score</span> de probabilidade de doen&#231;a em indiv&#237;duos com ECG de Brugada idiop&#225;tico ou em indiv&#237;duos com sintomas relacionados com arritmias e padr&#227;o de repolariza&#231;&#227;o tipo 2 ou 3 de Brugada&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Santos&#44; L&#59; Crit&#233;rios de diagn&#243;stico da S&#237;ndrome de Brugada&#46; Podemos melhorar&#63; Rev Port Cardiol&#46; 2012&#46; <span class="elsevierStyleInterRef" href="doi:10.1016/j.repc.2011.09.023">doi&#58;10&#46;1016&#47;j&#46;repc&#46;2011&#46;09&#46;023</span></p>"
      ]
    ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">A&#58; In healthy individuals&#44; there is a small notch in phase 1 of the ventricular action potential mediated by the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">TO</span> current that is more evident in the epicardium and is not visible on the ECG&#46; B&#58; In Brugada syndrome&#44; an ionic imbalance in phase 1 favoring repolarization in the epicardial surface generates a transmural voltage gradient&#44; seen on the ECG as type 1 repolarization pattern&#46;</p>"
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      1 => array:7 [
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">The fast response cardiac action potential is responsible for atrial &#40;green&#41;&#44; Purkinje &#40;purple&#41; and ventricular &#40;red&#41; depolarization and conduction&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Three repolarization patterns associated with BS&#46;</p>"
        ]
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Late potentials are defined by at least two of three criteria&#58; total filtered QRS duration &#40;fQRS&#41; &#62;114<span class="elsevierStyleHsp" style=""></span>ms&#44; the duration of the terminal QRS complex that is less than 40<span class="elsevierStyleHsp" style=""></span>&#956;V &#40;low amplitude signal &#91;LAS&#93;&#41; &#62;38<span class="elsevierStyleHsp" style=""></span>ms&#44; and the voltage in the last 40<span class="elsevierStyleHsp" style=""></span>ms of the QRS &#40;root-mean square &#91;RMS40&#93;&#41; &#60;20<span class="elsevierStyleHsp" style=""></span>&#956;V&#46;</p>"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ROC curve from the screening test &#40;ScreenTest&#41; and diagnostic test &#40;DiagTest&#41;&#46;</p>"
        ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atypical right bundle branch block&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Right ventricular myocardial infarction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acute pericarditis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemopericardium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulmonary thromboembolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aortic dissection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Central nervous system disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Duchenne muscular dystrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Friedreich&#39;s ataxia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Left ventricular hypertrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arrhythmogenic right ventricular cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mechanical compression of the right ventricular outflow tract &#40;tumor&#47;pectus excavatum&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Following electrical cardioversion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early repolarization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypothermia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab268767.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Clinical situations that can mimic the Brugada repolarization pattern&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ICD&#58; implantable cardioverter-defibrillator&#59; LAS&#58; low-amplitude signal&#59; PS&#58; PR interval<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>filtered QRS complex&#59; QTd&#58; QT dispersion&#59; RMS40&#58; root-mean-square&#59; SAECG&#58; signal-averaged ECG&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Carriers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Non-carriers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Association with <span class="elsevierStyleItalic">SCN5A</span> mutation &#40;eta coefficient&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Clinical and demographic characteristics</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male &#8211; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;47&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;47&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;567&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#46;31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#46;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;059&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Spontaneous type 1 ECG<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#8211; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;52&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Spontaneous type 2&#47;3 ECG<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> &#8211; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;11&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Provocation test &#8211; n total&#47;n positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#47;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;161&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Symptoms &#8211; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;112&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>EPS &#8211; n total&#47;n positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;461&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ICD &#8211; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;25&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ECG and SAECG</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">190&#46;98<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">151&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;653&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>QTd&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;472&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>fQRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">106&#46;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;544&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#46;92<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0&#46;401&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RMS40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">18<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;55&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">35&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;47&nbsp;\t\t\t\t\t\t\n
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            1 => array:3 [
              "identificador" => "tblfn0010"
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Clinical&#44; demographic and electrical characteristics of the study population&#46;</p>"
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      7 => array:7 [
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">BS&#58; Brugada syndrome&#59; LAS&#58; low-amplitude signal&#59; PS&#58; PR interval<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>filtered QRS complex&#59; QTd&#58; QT dispersion&#59; RMS40&#58; root-mean-square&#59; VF&#58; ventricular fibrillation&#59; VT&#58; ventricular tachycardia&#46;</p>"
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                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Type 2&#47;3 ECG&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>250 and QTd<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10 and LAS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>26 and RMS40<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>29&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Type 1 ECG in relative&#40;s&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Documented VF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Documented VT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>VF&#47;VT inducible by programmed electrical stimulation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Family history of sudden cardiac death at &#60;45 years old&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Syncope&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nocturnal agonal respiration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Probability of BS</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;8 points&#58; confirmed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>7 points&#58; highly probable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>6 points&#58; possible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;5 points&#58; unlikely&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria of Brugada syndrome&#46;</p>"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Right bundle branch block&#44; persistent ST segment elevation and sudden cardiac death&#58; a distinct clinical and electrocardiographic syndrome&#46; A multicenter report"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "P&#46; Brugada"
                            1 => "J&#46; Brugada"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
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                        "volumen" => "20"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1309182"
                            "web" => "Medline"
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              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Brugada syndrome&#58; report of the second consensus conference&#58; endorsed by the Heart Rhythm Society and the European Heart Rhythm Association"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "C&#46; Antzelevitch"
                            1 => "P&#46; Brugada"
                            2 => "M&#46; Borggrefe"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.CIR.0000152479.54298.51"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2005"
                        "volumen" => "111"
                        "paginaInicial" => "659"
                        "paginaFinal" => "670"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15655131"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Brugada syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46; Antzelevitch"
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                    0 => array:2 [
                      "doi" => "10.1111/j.1540-8159.2006.00507.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pacing Clin Electrophysiol"
                        "fecha" => "2006"
                        "volumen" => "29"
                        "paginaInicial" => "1130"
                        "paginaFinal" => "1159"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17038146"
                            "web" => "Medline"
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              "identificador" => "bib0020"
              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "Q&#46; Chen"
                            1 => "G&#46;E&#46; Kirsch"
                            2 => "D&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/32675"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1998"
                        "volumen" => "392"
                        "paginaInicial" => "293"
                        "paginaFinal" => "296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9521325"
                            "web" => "Medline"
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            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Brugada syndrome&#58; update 2009"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "P&#46; Brugada"
                            1 => "B&#46; Benito"
                            2 => "R&#46; Brugada"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Hellenic J Cardiol"
                        "fecha" => "2009"
                        "volumen" => "50"
                        "paginaInicial" => "352"
                        "paginaFinal" => "372"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19767278"
                            "web" => "Medline"
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              "identificador" => "bib0030"
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                0 => array:2 [
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                      "titulo" => "Sodium channel gene &#40;SCN5A&#41; mutations in 44 index patients with Brugada syndrome&#58; different incidences in familial and sporadic disease"
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                      "Revista" => array:5 [
                        "tituloSerie" => "Hum Mutat"
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Journal Information
Vol. 31. Issue 5.
Pages 355-362 (May 2012)
Visits
25568
Vol. 31. Issue 5.
Pages 355-362 (May 2012)
Original article
Open Access
Diagnostic criteria for the Brugada syndrome: Can they be improved?
Visits
25568
Luís Ferreira Santosa,
Corresponding author
luisferreirasantos@gmail.com

Corresponding author.
, Telmo Pereirab, Bruno Rodriguesa, Emanuel Correiaa, Davide Moreiraa, Luís Nunesa, António Costaa, Luís Elvasc, José Carlos Machadod,e, Sérgio Castedod,e, Carla Henriquesf, Ana Matosf, Oliveira Santosa
a Serviço de Cardiologia, Hospital São Teotónio, EPE Viseu, Viseu, Portugal
b Departamento de Cardiopneumologia, Escola Superior de Tecnologia da Saúde de Coimbra, Coimbra, Portugal
c Serviço de Cardiologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal
d IPATIMUP, Porto, Portugal
e Serviço de Genética Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
f Departamento de Matemática, Instituto Politécnico de Viseu, Viseu, Portugal
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Table 1. Clinical situations that can mimic the Brugada repolarization pattern.
Table 2. Clinical, demographic and electrical characteristics of the study population.
Table 3. Diagnostic criteria of Brugada syndrome.
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Abstract
Introduction

Diagnosis of Brugada syndrome (BS) currently requires documentation of a characteristic repolarization pattern (type 1 Brugada ECG). Mutations in the SCN5A gene, which codes for sodium channel NaV 1.5, are found in 38% of familial cases of BS. Sodium current dysfunction negatively affects the cardiac fast response action potential, particularly in atrial and ventricular myocytes and in the fast-conducting Purkinje system.

Objectives

To detect carriers of SCN5A mutations without using the characteristic repolarization pattern (type 1 Brugada ECG).

Methods

Of a total of 141 members of three different families including 55 carriers of two nonsense SCN5A mutations causing BS, all those aged over 16 (113 individuals, 42 carriers) were studied. The PR interval (PR) and QT dispersion (QTd) between leads V1 and V3 were measured on conventional ECG. Using signal-averaged ECG the total duration of the filtered QRS complex (fQRS), the root-mean-square (RMS40) and the low-amplitude signal (LAS) were measured. The following procedures were developed to detect carriers: (1) a screening test (ScreenTest) with PS (PR+fQRS)250 (250ms is 80% of the theoretical maximum in healthy individuals); and (2) a diagnostic test (DiagTest) for the simultaneous fulfillment of four conditions: PS250 and QTd10 and LAS>26 and RMS40 ≤29 (the latter two cut-offs are approximately 70% of the theoretical maximum in healthy carriers).

Results

Significant differences in PR, QTd, fQRS, RMS40 and LAS were found between carriers and non-carriers. The SCN5A gene was associated with all these variables, the strongest association being with PR. Both tests were applied to 63 family members (38 carriers). The ScreenTest was positive in 38 of 38 carriers, with eight false positives in 27 non-carriers (sensitivity [SE]=100% and specificity [SP]=66.67%). From ROC curve analysis a cut-off of PS=252.5 shows SE=100% and SP=76% and a cut-off of PS=260 shows SE=94.7% and SP=84%. The DiagTest was positive in 36 of 38 carriers, with three false positives: SE=94.74% and SP=88.89%. From ROC curve analysis a multivariate logistic model identifies a cut-off with SE=92% and SP=92%. In the same group the SE and SP of the characteristic spontaneous repolarization pattern (type 1 Brugada ECG) to detect carriers were 52.4% and 97.2%, respectively, and the difference between the SE of the DiagTest and of the typical repolarization pattern is statistically significant.

Conclusions

The ScreenTest and DiagTest are more effective tools than the characteristic repolarization pattern to discriminate between carriers and non-carriers of these two nonsense SCN5A mutations. We suggest their use in first-degree relatives of Brugada patients when the results of genetic testing are not available, in a score of disease probability in individuals with idiopathic Brugada ECG, and in patients with arrhythmias or other Brugada-related symptoms presenting type 2 or type 3 Brugada ECG.

Keywords:
Brugada syndrome
Diagnostic score
SCN5A gene
Resumo
Introdução

Atualmente, o diagnóstico da Síndrome de Brugada (SB) obriga à documentação do padrão eletrocardiográfico de repolarização característico denominado tipo 1. Em 38% dos casos familiares desta entidade encontra-se uma mutação do gene SCN5A responsável pela síntese do canal de sódio NaV1.5. A disfunção desta corrente de sódio repercute-se no potencial de ação cardíaco de resposta rápida, fundamentalmente nos miócitos auriculares, nas fibras de Purkinje e nos miócitos ventriculares.

Objetivos

Detetar portadores de mutação do SCN5A sem recorrer ao padrão de repolarização no ECG.

Métodos

A partir de 3 famílias e de um total de 141 elementos, dos quais 55 portadores (P+) de duas mutações non-sense específicas do SCN5A causadoras de SB, foram estudados os maiores de 16 anos (113 elementos/42 P+). Foi medido no ECG o intervalo PR (PR) em DII e dispersão QT (dQT) entre V1 e V3. No ECG de alta resolução (ECGAR) determinado o QRS filtrado (QRSf), root-mean square (RMS40) e low-averaged signal (LAS). Para detetar P+ foi criado: 1) um teste de rastreio (TesteRas) constituído pelo intervalo PS (PR+QRSf)250 (250ms corresponde a 80% do valor teórico máximo deste intervalo em saudáveis) e 2) um teste diagnóstico (TesteDx) que resulta do cumprimento simultâneo de 4 condições: PS250 e dQT>10 e LAS26 e RMS4029 (estes 2 últimos valores correspondem aproximadamente a 70% do valor teórico máximo em saudáveis).

Resultados

Encontradas diferenças significativas entre os P+ versus não portadores (P-) do PR, da dQT, do QRSf, do LAS e da RMS40. O gene está associado a todas estas variáveis, sendo a associação mais forte com o PR. A 63 elementos (38 P+) foi aplicado o TesteRas e o TesteDx. O TesteRas foi positivo em 38 de 38 P+ com 8 falsos positivos em 27 P- (sensibilidade [S]=100% e especificidade [E]=66,67%). Na curva Roc para este teste o cut-off PS=252,5 tem S=100% e E=76% e o cut-off PS=260 tem S=94,7% e E=84%. O TesteDx foi positivo em 36 de 38 P+ com 3 falsos positivos: S=94,74% e E=88,89%. Por modelo logístico multivariado identifica-se um cut-off através da curva Roc com S=92% e E=92%. A S e E de diagnóstico do ECG espontâneo usando o padrão de repolarização tipo 1 no mesmo grupo de doentes foram de 52,4% e 97,2%, respetivamente (a diferença de S entre o TesteDx e o padrão de repolarização no ECG é estatisticamente significativa).

Conclusões

O TesteRas e o TesteDx são uma ferramenta mais eficaz do que o padrão de repolarização típico para distinguir entre P+ e P- destas duas mutações non-sense do SCN5A. Sugerimos a sua utilização em familiares diretos de casos índice com SB, quando o resultado genético (ainda) não está disponível e num score de probabilidade de doença em indivíduos com ECG de Brugada idiopático ou em indivíduos com sintomas relacionados com arritmias e padrão de repolarização tipo 2 ou 3 de Brugada.

Palavras-chave:
Síndrome de Brugada
Score diagnóstico
SCN5A
Full Text
Introduction

Brugada syndrome (BS) was first described as a new entity in 1992. It has a characteristic electrocardiographic pattern (right bundle branch block and ST-segment elevation in the right precordial leads) and is associated with increased risk for malignant ventricular arrhythmias and sudden death in individuals without structural heart disease.1 In two decades it has ceased to be a medical curiosity and has become an entity that must be diagnosed, stratified and treated, since it is estimated to be responsible for 20–50% of cases of sudden death in individuals with structurally normal hearts,2 and the mean age at diagnosis and/or the event that prompts it (which is often sudden death) is 40±22 years. BS belongs to the group of channelopathies, diseases that are caused by primary dysfunction of the ion channels responsible for cardiac action potentials, which triggers or perpetuates arrhythmias without concomitant structural disease.3

Historical perspective

BS is a congenital disease and familial transmission is frequent. The first mutation associated with BS, in the SCN5A gene which codes for the α subunit of the cardiac sodium channel NaV 1.5,4 was described in 1998, and since then over 100 different mutations in this gene have been reported.5 These mutations may be nonsense or missense, and not all have the same pathophysiological effects. The former are usually more serious, as they produce a truncated protein that is dysfunctional because it is a different length than normal. Missense mutations cause substitution of an amino acid but the protein remains complete. In this case the biological effects on protein function are unclear, and in vitro functional studies are needed to ascertain their importance.

Mutations in the SCN5A gene can lead to a decrease in sodium current (INa) in the cardiac action potential, either through quantitative decrease (failure in expression) or through qualitative dysfunction of the channel. However, mutations are found in only 18–30% of patients2 and in only 38% of familial cases.6 This low incidence may be explained by genetic heterogeneity, i.e. mutations in other genes that are associated with BS, as well as many others presumably yet to be discovered, including: (1) GPD1-L, the gene that codes for glycerol-3-phosphate dehydrogenase 1 like peptide, which is responsible for the transport of NaV1.5 to the cell surface and, when mutated, leads to a 31% reduction in the quantity of channels available in the membrane and a 50% reduction in sodium current, resulting in BS7; (2) mutations in cardiac calcium channel genes (CACNA1c and CACNB2b) associated with an overlapping entity, short QT syndrome with Brugada ECG pattern8; and (3) mutations in the KCNE3 gene, which modulates the function of the KV4.3 channel, which is responsible for the transient potassium outward current (ITO).9 Apart from those recently described in the SCN5A gene, all these mutations have made it necessary to widen the original idea of BS as a “pure” sodium channelopathy to the currently accepted concept of it as a channelopathy of phase 1 of the cardiac action potential due to an imbalance in one of the different ion currents (sodium, potassium or calcium), caused by mutations in either ion channel genes or in genes coding for proteins associated with the activity or transport of these currents.10

Diagnosis of BS

Diagnosis of BS is currently only considered definitive when a type 1 Brugada ECG pattern is observed in at least two right precordial leads, in the presence or absence of a sodium-channel blocking agent, in conjunction with one or more of the following: documented ventricular fibrillation (VF), documented ventricular tachycardia (VT), a family history of sudden cardiac death at <45 years old, type 1 ECG in family members, inducibility of VF/VT with programmed electrical stimulation in electrophysiological study, syncope, or nocturnal agonal respiration.2

From gene to electrocardiogram

There are two theories to explain the electrocardiographic manifestations of BS: (1) delayed conduction in the free wall epicardium of the right ventricular outflow tract; (2) premature repolarization of the right ventricular epicardial action potential; or a combination of the two. In the first, asynchronous activation of the epicardium in relation to the endocardium, due to dysfunction of an ion channel (NaV1.5 or another), creates a voltage gradient between the two layers of cells. In the second (Fig. 1), dysfunction of a channel (NaV1.5 or another) leads to an imbalance in phase 1 that favors repolarization due to the disproportionate ITO current (positive outward current), with the result that the membrane repolarizes beyond the voltage at which L-type calcium channels are activated and phase 2 of the action potential thus fails. In both models a transmural voltage gradient is generated between the epicardium and the endocardium that appears on the ECG as a coved ST-segment elevation of ≥2mm (0.2mV), followed by a negative T wave (type 1 Brugada ECG) that acts as an arrhythmic substrate for phase 2 reentry. Both hypotheses explain the preferential involvement of the right ventricular outflow tract since the ITO current has greater functional expression in the epicardium of this region. The repolarization alterations on the ECG that are diagnostic of BS reflect dysfunction of the ventricular fast response action potential, which is also responsible for depolarization of atrial myocytes and Purkinje fibers (Fig. 2).11,12 It can therefore be hypothesized that the action potential dysfunction responsible for the repolarization disturbances described above may also lead to increases, or even subclinical or clinical disturbances, in intra-atrial, atrioventricular and intraventricular conduction.

Figure 1.

A: In healthy individuals, there is a small notch in phase 1 of the ventricular action potential mediated by the ITO current that is more evident in the epicardium and is not visible on the ECG. B: In Brugada syndrome, an ionic imbalance in phase 1 favoring repolarization in the epicardial surface generates a transmural voltage gradient, seen on the ECG as type 1 repolarization pattern.

(0.2MB).
Figure 2.

The fast response cardiac action potential is responsible for atrial (green), Purkinje (purple) and ventricular (red) depolarization and conduction.

(0.3MB).
Difficulties in the diagnosis of BS

A diagnosis of BS is simple in its most characteristic form of presentation, i.e. spontaneous type 1 repolarization pattern in the right precordial leads together with aborted cardiac arrest. Type 1 repolarization pattern with no other criteria should be described as idiopathic Brugada ECG (not Brugada syndrome), and there is considerable controversy concerning the appropriate clinical approach. A wide range of differential diagnoses that can mimic the BS ECG alterations should be considered (Table 1),5 but it should be borne in mind that the first symptom that confirms a diagnosis of BS may be catastrophic: cardiac arrest is the first manifestation in 77% of patients. There are also difficulties with diagnosis in cases of borderline or Brugada-like repolarization patterns. Besides type 1 Brugada ECG, there are two other repolarization patterns associated with BS (Fig. 3): type 2 (≥2mm J-point elevation, downsloping ST segment but at least 1mm above the isoelectric line, and positive or biphasic (‘saddle-back’) T wave; and type 3, with ≥2mm J-point elevation and <1mm ST-segment elevation, coved or saddle-back or both. According to the consensus conference on Brugada syndrome, types 2 and 3 are merely suggestive and not diagnostic, a recommendation that is not followed by all authors.13,14 Whether only type 1, or all three types of pattern, are taken to be diagnostic obviously affects the sensitivity and specificity of the ECG to detect BS, sensitivity being greater when all three are used and specificity being higher with only type 1. Type 3 pattern is virtually indistinguishable from the incomplete right bundle branch block found in the young; disregarding it could have catastrophic results, but an incorrect diagnosis of BS would place an enormous burden on a healthy individual and their family, with serious consequences for their personal, social, and professional life. This dilemma has aroused controversy in the literature and is presumed to have “contaminated” some databases with healthy individuals, which would explain the significant differences in reported prognosis for this entity.15–17

Table 1.

Clinical situations that can mimic the Brugada repolarization pattern.

Atypical right bundle branch block 
Right ventricular myocardial infarction 
Acute pericarditis 
Hemopericardium 
Pulmonary thromboembolism 
Aortic dissection 
Central nervous system disorders 
Duchenne muscular dystrophy 
Friedreich's ataxia 
Left ventricular hypertrophy 
Arrhythmogenic right ventricular cardiomyopathy 
Mechanical compression of the right ventricular outflow tract (tumor/pectus excavatum) 
Following electrical cardioversion 
Early repolarization 
Hypothermia 
Figure 3.

Three repolarization patterns associated with BS.

(0.13MB).

When diagnosis is confirmed in any index case, all family members who might be affected should be tested with baseline ECG and/or provocation testing. Baseline ECG alone is insufficient, since 51% of affected individuals fluctuate between diagnostic and non-diagnostic ECGs.18 Provocation testing with sodium channel blockers such as flecainide, ajmaline or procainamide is thus essential to detect intermittent or occult forms of the disease, although little is known of their sensitivity, specificity and reproducibility.19

Signal-averaged ECG

Signal-averaged ECG (SAECG) is a computer-based technique that is able to detect QRS abnormalities that are too subtle for conventional ECG. This exam (Fig. 4) shows the arithmetic mean of the sum of multiple (usually 200) QRS complexes, obtained over a period of approximately five minutes with as little background noise as possible. The process increases the signal-to-noise ratio of the selected cardiac complexes so that signals of the order of one microvolt in the terminal QRS complex can be detected and measured to within a few milliseconds. These signals are commonly known as ventricular late potentials.20

Figure 4.

Late potentials are defined by at least two of three criteria: total filtered QRS duration (fQRS) >114ms, the duration of the terminal QRS complex that is less than 40μV (low amplitude signal [LAS]) >38ms, and the voltage in the last 40ms of the QRS (root-mean square [RMS40]) <20μV.

(0.08MB).
Objectives

The aims of the study were to construct a model to detect carriers of nonsense or missense SCN5A mutations with significant functional repercussions based on subclinical disturbances in intra-atrial, atrioventricular and intraventricular conduction. This is used to develop a score of disease probability which we suggest should be used in first-degree relatives of Brugada patients and in individuals with idiopathic Brugada ECG.

Methods

Of a total of 141 members of three different families including 55 carriers of two nonsense SCN5A mutations causing BS (43 with Arg222STOP and 12 with Thr1754ProfsX32), all those aged over 16 were studied.

The PR interval (PR) in DII and QT dispersion (QTd) between leads V1 and V3 were measured on conventional ECG, calibrated so that 20mm=1mV, and with a velocity of 50mm/s. Signal-averaged ECG was performed with time-domain analysis, and the total duration of the filtered QRS complex (fQRS), the root-mean-square (RMS40) and the low-amplitude signal (LAS) were measured. Two tests were developed to detect carriers:

(1) a screening test (ScreenTest) with PS (the sum of PR and fQRS)250 (the theoretical maximum of this interval in healthy individuals is 314ms [200+114], 250ms being 80% of this figure);

(2) a diagnostic test (DiagTest) for the simultaneous fulfillment of four conditions: PS250 and QTd>10 and LAS>26 and RMS4029 (the latter two cut-offs are approximately 70% of the theoretical maximum in healthy carriers).

Results

The study population consisted of 113 individuals, 42 of them carriers. Significant differences in PR, QTd, fQRS, RMS40 and LAS were found between carriers and non-carriers. The SCN5A gene was associated with all these variables, the strongest association being with PR (Table 2). Both tests were applied to 63 family members (38 carriers). The ScreenTest was positive in 38 of 38 carriers, with eight false positives in 27 non-carriers (sensitivity=100% and specificity=66.67%). From ROC curve analysis (Fig. 5) a cut-off of PS=252.5 shows sensitivity=100% and specificity=76% and a cut-off of PS=260 shows sensitivity=94.7% and specificity=84%. The DiagTest was positive in 36 of 38 carriers, with three false positives: sensitivity=94.74% and specificity=88.89%. From ROC curve analysis a multivariate logistic model identifies a cut-off with sensitivity=92% and specificity=92%. The area under the curve was 0.927 (p<0.001), demonstrating that this test has an excellent ability to discriminate between carriers and non-carriers.21 In the same group the sensitivity and specificity of the characteristic spontaneous repolarization pattern (type 1 Brugada ECG) to detect carriers were 52.4% and 97.2%, respectively, and the difference between the sensitivity of the DiagTest and of the typical repolarization pattern is statistically significant.

Table 2.

Clinical, demographic and electrical characteristics of the study population.

  Carriers  Non-carriers  Association with SCN5A mutation (eta coefficient) 
Clinical and demographic characteristics
Male – n (%)  20 (47.6)  34 (47.9)  0.567  – 
Age (years)  40.31±14.81  35.08±13.05  0.059  – 
Spontaneous type 1 ECGa – n (%)  22 (52.4)  2 (2.8)  <0.001  – 
Spontaneous type 2/3 ECGb – n (%)  5 (11.9)  4 (5.6)  0.490  – 
Provocation test – n total/n positive  17/8  10/2  0.161  – 
Symptoms – n (%)  6 (14.3)  4 (5.6)  0.112  – 
EPS – n total/n positive  18/3  5/0  0.461  – 
ICD – n (%)  8 (25.8)  –  –  – 
ECG and SAECG
PR  190.98±27.09  151.37±22.18  <0.001  0.653 
QTd  47.14±23.51  28.95±18.04  <0.001  0.472 
fQRS  106.13±9.40  92.41±10.76  <0.001  0.544 
LAS  41.92±9.75  31.59±11.82  <0.001  0.401 
RMS40  18±6.55  35.26±21.8  <0.001  0.47 

ICD: implantable cardioverter-defibrillator; LAS: low-amplitude signal; PS: PR interval+filtered QRS complex; QTd: QT dispersion; RMS40: root-mean-square; SAECG: signal-averaged ECG.

a

Patients with at least one type 1 ECG.

b

Patients with at least one type 2/3 ECG and no type 1.

Figure 5.

ROC curve from the screening test (ScreenTest) and diagnostic test (DiagTest).

(0.14MB).
Discussion

In 2008 it was demonstrated that carriers of truncating (nonsense) SCN5A mutations have more symptomatic forms of BS, and atrioventricular conduction disturbances were also described, both through increased PR interval22,23 and increased HV interval measured invasively during electrophysiological study.24 SAECG was proposed around the same time as a possible tool for arrhythmic risk stratification in BS.25

However, this study is the first to propose incorporating conduction parameters into the diagnostic process. As with long QT syndrome26 and arrhythmogenic right ventricular cardiomyopathy,27 the proposed test could be included in a score of disease probability (Table 3), which we consider would be useful given the shortcomings discussed above of using patterns of ventricular repolarization in isolation and the clinical and social burdens arising from a diagnosis of BS.

Table 3.

Diagnostic criteria of Brugada syndrome.

Criterion  Points 
ECG
Type 1 ECG 
Type 2/3 ECG 
PS250 and QTd>10 and LAS26 and RMS4029 
Type 1 ECG in relative(s) 
Documented VF 
Documented VT 
VF/VT inducible by programmed electrical stimulation 
Clinical features
Family history of sudden cardiac death at <45 years old 
Syncope 
Nocturnal agonal respiration 
Probability of BS
≥8 points: confirmed   
7 points: highly probable   
6 points: possible   
≤5 points: unlikely   

BS: Brugada syndrome; LAS: low-amplitude signal; PS: PR interval+filtered QRS complex; QTd: QT dispersion; RMS40: root-mean-square; VF: ventricular fibrillation; VT: ventricular tachycardia.

When there is clinical and/or electrocardiographic suspicion of BS, intra-atrial, atrioventricular and intraventricular conduction times should be measured, ideally with SAECG, since the fast response cardiac action potential that is dysfunctional in BS is involved in all three. Simultaneous detection of times above the normal-high limit of these three depolarization times (in this study the limit used was 70–80% of the theoretical maximum in healthy individuals) may indicate the likelihood of the individual having the disease due to nonsense or missense mutations in SCN5A with significant functional impact. We suggest their use in adult first-degree relatives of index cases when the results of genetic testing are not available. Another possible use would be to calculate the probability of disease in individuals with idiopathic Brugada ECG or with arrhythmias and type 2 or 3 Brugada repolarization pattern. In these cases, the proposed score could support the diagnosis (score 7), raise suspicion (score 6), or render it unlikely (score ≤5).

Conclusion

We have shown that the ScreenTest and DiagTest are more effective tools than the characteristic Brugada repolarization pattern to discriminate between carriers and non-carriers of nonsense SCN5A mutations.

These tests may be useful in diagnosing this entity by determining the probability that a given repolarization pattern in fact corresponds to BS.

Limitations

Our study has two major limitations:

  • 1.

    The number of carriers was relatively small and only two mutations were studied. In order to prove the usefulness and reproducibility of the proposed score, it will be necessary to apply it to other Brugada patients and their families.

  • 2.

    The P wave and the PR interval were not measured with the precision of SAECG, since the means to do so were not available to our group. Measurement of the PS interval, or the PR+fQRS wave, entirely by SAECG (without interference from the atrioventricular node) could make the score even more effective.

We accordingly urge all clinicians working with BS patients who may be interested in collaborating with this work to contact us.

Conflicts of interest

The authors have no conflicts of interest to declare.

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Please cite this article as: Santos, L; Critérios de diagnóstico da Síndrome de Brugada. Podemos melhorar? Rev Port Cardiol. 2012. doi:10.1016/j.repc.2011.09.023

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